CN108341771A - A kind of preparation method of 3- cyano -2,6- dihydroxy-pyridine sodium hydrates - Google Patents
A kind of preparation method of 3- cyano -2,6- dihydroxy-pyridine sodium hydrates Download PDFInfo
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- CN108341771A CN108341771A CN201710044886.3A CN201710044886A CN108341771A CN 108341771 A CN108341771 A CN 108341771A CN 201710044886 A CN201710044886 A CN 201710044886A CN 108341771 A CN108341771 A CN 108341771A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
Abstract
The present invention provides a kind of preparation method of 2,6 dihydroxy-pyridine sodium hydrate of 3 cyano, which can further prepare 3 cyano, 2,6 dihydroxy-pyridine or its monohydrate.Since 3 cyano, 2, the 6 dihydroxy-pyridine sodium hydrate purity being prepared is very high, thus, very high 3 cyano, 2,6 dihydroxy-pyridine of purity or its monohydrate just can be prepared after adjusting acid or adding water tune acid.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of 3-cyano-2,6-dihydroxypyridine sodium hydrate.
Background technology
Periodical literature Chem.Pharm.Bull.41 (9) 1498- of 3- cyano -2,6- dihydroxy-pyridines in 1993
It is disclosed in 1506, Vol.41, No.9, structural formula is as follows：
Preparation is reacted in alkali with cyanoacetamide by 1,3- dimethyl uracils.In last handling process, five oxidations two are used
Phosphorus goes drying, thus, the 3-cyano-2,6-dihydroxypyridine sodium being prepared does not contain the crystallization water.
WO2007109459 discloses a kind of preparation method of 3- cyano -2,6-- dihydroxy-pyridine sodium, by ethyl propiolate
Preparation is reacted in alkali with cyanoacetamide.Anhydrous process, solvent methanol is required also to require drying anhydrous in entire reaction process, because
And 3- cyano -2, the 6-- dihydroxy-pyridine sodium being prepared does not contain the crystallization water.
The above-mentioned preparation about 3-cyano-2,6-dihydroxypyridine and its sodium salt in the prior art is all that requirement is preferably
Water-free product can be directly obtained, if containing water, also requirement goes drying with drier.The present invention is just and this idea
Different, the present invention is that sodium-salt hydrate is first prepared, rear to adjust acid or prepare 3- cyano -2,6- dihydroxy pyrroles after adding water tune acid
Pyridine or its monohydrate.Thus, it is unlike the prior art, also not obtain a kind of method of technical inspiration from the prior art.
Invention content
The present invention provides 3-cyano-2,6-dihydroxypyridine sodium hydrate preparation methods, are a low raw-material costs,
Safety and environmental protection, product yield is high, and purity is high, is suitble to the route of industrialized production.
In order to realize the technical purpose of the present invention, the technical solution adopted by the present invention is：
It prepares 3-cyano-2,6-dihydroxypyridine sodium hydrate and specifically prepares its dihydrate, it is phonetic by the urine replaced
Acridine compound is reacted with formula F compounds.
Wherein, R is alkyl, aryl, substituted aryl, naphthenic base, heteroaryl.The aryl is preferably benzene, and substituted aryl is excellent
It is selected as benzyl, the heteroaryl can be pyridine, pyrimidine, furans, thiophene or indoles.R2ForOr
Preferably, the uracil compound replaced shown in formula I is reacted with formula F compounds prepares 3- cyano -2,6- bis-
Pyridone sodium dihydrate.
Wherein, R1Can be hydrogen, alkyl or alkoxy.Preferably, R1For hydrogen, R2Definition it is same as described above.
Preferably, the uracil compound replaced shown in formula I -1 is reacted with formula F compounds prepares 3- cyano -2,6-
Dihydroxy-pyridine sodium dihydrate.
Wherein, R1Can be hydrogen, alkyl or alkoxy.Preferably, R1For hydrogen.
Further, above-mentioned substituted uracil compound is prepared in the presence of alkali with reacting for formula F compounds.
The alkali can be organic base or inorganic base, and the organic base is preferably sodium alkoxide, it is highly preferred that being methanol
Sodium, sodium ethoxide or sodium tert-butoxide.The inorganic base can be sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus or sodium hydride.
The reaction dissolvent is alcohols solvent, it is preferable that is methanol, ethyl alcohol or the tert-butyl alcohol.
The reaction temperature is 0 DEG C~80 DEG C.
The uracil compound that replaces shown in the formula I -1, formula F compounds, the molar ratio range of alkali are 1:(0.5~
3):(0.5:3) it is preferably, 1:1.1:2.5.
The above-mentioned substituted uracil compound of the present invention occurs substitution reaction by uracil and alkyl halide compound and prepares, instead
Answer formula as follows：
Specifically, the uracil compound replaced shown in formula I -1 is by uracil and halogenated aryl hydrocarbon or derivatives thereof through taking
Prepared by generation reaction, reaction equation is as follows：
Wherein, R, R1Definition it is same as described above, X is halogen, and preferably, X is chlorine.
Above-mentioned substitution reaction carries out under the action of alkali and phase transfer catalyst.
The alkali can be organic base or inorganic base.The organic base is sodium alkoxide, is sodium methoxide preferably.The nothing
Machine alkali is sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus or sodium hydride.
The phase transfer catalyst can be 18- crown ethers -6,18- crown ethers -5, TEBA, TBAB, TBAF or PEG400.
The molar ratio range of the uracil and alkyl halide compound is (1:0.5)~(1:4), preferred proportion 1:2.5
More preferably ratio is 1:2.1.
The molar ratio range of uracil and alkali is (1:0.5)~(1:4), preferred proportion 1:3.0, more preferably ratio 1:
2.5。
In above-mentioned reaction, the reaction dissolvent can be polar non-solute, the polar non-solute be acetonitrile,
Acetone, DMF, DMAC, DMI, NMP, HMP or DMSO etc..
The 3-cyano-2,6-dihydroxypyridine sodium hydrate that the present invention is prepared is detected as dihydrate, liquid through TGA
Phase chromatographic purity is more than 99.0%.
3- cyanogen can be prepared after adjusting acid in the 3- cyano -2,6- dihydroxy-pyridine sodium dihydrates that the present invention is prepared
Base -2,6- dihydroxy-pyridines.If rear to adjust acid, moreover it is possible to 3-cyano-2,6-dihydroxypyridine monohydrate be prepared through adding water.
Since 3-cyano-2,6-dihydroxypyridine sodium dihydrate purity is very high, thus, it can also obtain the very high 3- cyanogen of purity
Base -2,6- dihydroxy-pyridines and its monohydrate.
3- cyano -2,6- dihydroxy-pyridines of the present invention and its monohydrate prepare can by the uracil compound that replaces with
Through adjusting acid or warp plus water after formula F compounds reaction preparation 3-cyano-2,6-dihydroxypyridine sodium hydrate, acid preparation is adjusted afterwards, instead
Answer formula as follows：
Wherein, R, R2Definition it is same as described above.
Above-mentioned tune acid process, the acid used are inorganic acid, and the inorganic acid can be hydrochloric acid, sulfuric acid, phosphoric acid, can also be
Methanesulfonic acid or p-methyl benzenesulfonic acid etc. are preferably hydrochloric acid.
The present invention provides 3-cyano-2,6-dihydroxypyridine sodium hydrate preparation methods, are a low raw-material costs,
Safety and environmental protection, product yield is high, and purity is high, is suitble to the route of industrialized production.Low raw-material cost is mainly reflected in and methyl
In the comparison of uracil.Methyluracil can not be purchased largely on the market, if synthesis, can use the sulfuric acid two to severe toxicity
Methyl esters.Such as periodical literature Journal of the American Chemical Society, 136 (19), 6920-6928；
Synthesizing methyl uracil has just used the dimethyl suflfate of severe toxicity in 2014.In addition, due in the prior art about 3- cyanogen
The preparation of base -2,6- dihydroxy-pyridine and its sodium salt is all that requirement is desirable to directly obtain water-free product, if contained
Water also requires to go drying with strong dehydrating agent such as phosphorus pentoxide.
Phosphorus pentoxide belongs to high-risk chemical, uses than relatively hazardous.And the present invention does not use dangerous material, play
Drugs, operation is simpler, safe, and products obtained therefrom quality is high.
Also, the present invention is just otherwise-minded with this, and the present invention is that sodium-salt hydrate is first prepared, rear to adjust acid
Or water tune acid is added to prepare 3- cyano -2,6- dihydroxy-pyridines or its hydrate.Thus, it is unlike the prior art, also not from existing
There is technology to obtain a kind of method of technical inspiration.
Description of the drawings
Fig. 1 is the TGA collection of illustrative plates of 3-cyano-2,6-dihydroxypyridine sodium dihydrate,
Fig. 2 is the HPLC collection of illustrative plates of 3-cyano-2,6-dihydroxypyridine sodium dihydrate,
Fig. 3 is the TGA collection of illustrative plates of 3-cyano-2,6-dihydroxypyridine,
Fig. 4 is the TGA collection of illustrative plates of 3-cyano-2,6-dihydroxypyridine monohydrate,
Fig. 5 is the hydrogen nuclear magnetic spectrum of 3-cyano-2,6-dihydroxypyridine sodium dihydrate,
Fig. 6 is the hydrogen nuclear magnetic spectrum of 3- cyano -2,6- dihydroxy-pyridines.
Specific implementation mode
For a further understanding of the present invention, with reference to embodiment to 3- cyano -2,6- dihydroxy pyrrole provided by the invention
Pyridine sodium hydrate and preparation method thereof is described in detail.It is to be appreciated that the description of these embodiments is only further detailed
Describe the feature of the bright present invention in detail, rather than to the limitation of the scope of the invention or scope of the invention as claimed.
Embodiment 1：
Acetonitrile 1000mL, uracil 100g, benzyl chloride 237g (2.1eq), potassium carbonate are put into 2000L reaction bulbs
308.3g (2.5eq), -6 7g of 18- crown ethers (0.03eq) open stirring.40~82 DEG C are slowly ramped to, insulation reaction is until anti-
Should be complete, reaction solution is cooled to 20~30 DEG C, is filtered, filter cake is eluted with appropriate acetonitrile.Filtrate decompression is added while hot to after doing
Enter isopropanol 500mL, -5~0 DEG C is slowly cooled to again after stirring dissolved clarification, keeps the temperature analysis of material 2h, filtering, the appropriate isopropanol of filter cake
Elution, then filter to dry.35~40 DEG C of vacuum dryings of vacuum drying oven, obtain 238.7g white solids 1, and 3- dibenzyl uracils are received
Rate 91.5%.
Embodiment 2：
It is molten that 1,3- dibenzyl uracils 160g, cyanoacetamide 55.2g (1.2eq), sodium methoxide are added in 2000L reaction bulbs
Liquid 256.6g (2.5eq), methanol 800mL open stirring.45~50 DEG C are warming up to, insulation reaction 6 hours, TLC detections have been reacted
Reaction solution is cooled to 20~30 DEG C after complete, is filtered, filter cake is eluted with proper amount of methanol.In 2000L reaction bulbs put into filter cake and
800g water.70~75 DEG C are warming up to, then slow cooling to 0~5 DEG C of heat preservation crystallization 2h, filtering, filter cake are eluted with appropriate ice water,
Obtain 3-cyano-2,6-dihydroxypyridine sodium dihydrate 94.0g, yield 88.5%, HPLC purity 99.6%, TGA collection of illustrative plates
See that Fig. 1, HPLC collection of illustrative plates are shown in Fig. 2,1H NMR spectras are shown in Fig. 5.1HNMR solvents：DMSO, primary standard substance：TMSδ(ppm)：4.99~
5.02 (1H, d, CH- pyridine rings), 7.09~7.11 (1H, d × d, CH pyridine rings), 9.81 (1H, s, OH).
Embodiment 3：
It is molten that 1,3- dibenzyl uracils 160g, cyanoacetamide 55.2g (1.2eq), sodium methoxide are added in 2000L reaction bulbs
Liquid 256.6g (2.5eq), methanol 800mL open stirring.45~50 DEG C are warming up to, insulation reaction 6 hours, TLC detections have been reacted
Reaction solution is cooled to 20~30 DEG C after complete, is filtered, filter cake is eluted with proper amount of methanol.In 2000L reaction bulbs put into filter cake and
800g water.70~75 DEG C are warming up to, then slow cooling to 0~5 DEG C of heat preservation crystallization 2h, filtering, filter cake are eluted with appropriate ice water,
Filter cake is 2,6- dihydroxy nicotinic acid nitrile mono-sodium salt dihydrates.20~30 DEG C of temperature control slowly puts into filter cake in aqueous hydrochloric acid solution
(480g water and 66.6g concentrated hydrochloric acids).20~30 DEG C of heat preservation crystallization 1h are further continued for being cooled to 0~5 DEG C of heat preservation crystallization 2h, filter, filter
Cake is eluted with appropriate ice water.Filter cake drying after 74.5g white solid 3-cyano-2,6-dihydroxypyridine, yield 86.5%,
Its1H NMR spectras are shown in Fig. 6.1H NMR solvents：DMSO, primary standard substance：TMSδ(ppm)：5.67~5.70 (1H, d, CH- pyridine rings),
7.82~7.84 (1H, d, CH- pyridine rings), 12.28 (2H, s, OH).
Embodiment 4：
It is molten that 1,3- dibenzyl uracils 160g, cyanoacetamide 55.2g (1.2eq), sodium methoxide are added in 2000L reaction bulbs
Liquid 256.6g (2.5eq), methanol 800mL open stirring.45~50 DEG C are warming up to, insulation reaction 6 hours, TLC detections have been reacted
Reaction solution is cooled to 20~30 DEG C after complete, is filtered, filter cake is eluted with proper amount of methanol.In 2000L reaction bulbs put into filter cake and
800g water.70~75 DEG C are warming up to, then slow cooling to 0~5 DEG C of heat preservation crystallization 2h, filtering, filter cake are eluted with appropriate ice water,
Filter cake is 2,6- dihydroxy nicotinic acid nitrile mono-sodium salt dihydrates.Pure water 300mL is added in reaction bulb, puts into the filter cake, then uses
Hydrochloric acid adjusts pH=2~4, and crystallization 1h is kept the temperature in 20~30 DEG C, is further continued for being cooled to 0~5 DEG C of heat preservation crystallization 2h, filter, filter cake
It is eluted with appropriate ice water.73.0g white solid 3-cyano-2,6-dihydroxypyridine monohydrates, yield are obtained after filter cake drying
86.5%.Its TGA collection of illustrative plates is shown in Fig. 4.
Claims (10)
1. a kind of 3-cyano-2,6-dihydroxypyridine sodium dihydrate, structural formula are as follows：
2. a kind of preparation method of 3-cyano-2,6-dihydroxypyridine sodium dihydrate, which is characterized in that by the uracil replaced
Compound reacts preparation with formula F compounds,
Wherein, R is alkyl, aryl, substituted aryl, naphthenic base, heteroaryl, R2For
3. preparation method according to claim 2, which is characterized in that the alkyl is methyl, and the aryl is phenyl, institute
It is benzyl to state substituted aryl, and the heteroaryl is pyridine, pyrimidine, furans, thiophene or indoles.
4. a kind of preparation method of 3-cyano-2,6-dihydroxypyridine sodium dihydrate, which is characterized in that taken shown in formula I
The uracil compound in generation is reacted with formula F compounds prepares 3-cyano-2,6-dihydroxypyridine sodium dihydrate,
Wherein, R1For hydrogen, alkyl or alkoxy, R2Definition it is identical as claim 2.
5. preparation method according to claim 2, which is characterized in that the substituted uracil compound is passed through by uracil
Prepared by substitution reaction, reaction equation is as follows：
Wherein, the definition of R is identical with claim 2.
6. a kind of preparation method of 3-cyano-2,6-dihydroxypyridine, which is characterized in that by the uracil compound and formula replaced
The reaction of F compounds is prepared after preparing 3-cyano-2,6-dihydroxypyridine sodium dihydrate through tune acid, and reaction equation is as follows：
Wherein, the definition of R is identical as in claim 2.
7. a kind of preparation method of 3-cyano-2,6-dihydroxypyridine monohydrate, which is characterized in that by the uracil replaced
After conjunction object reacts preparation 3-cyano-2,6-dihydroxypyridine sodium dihydrate with formula F compounds, Xian Jiashui is prepared by tune acid,
Reaction equation is as follows：
Wherein, the definition of R is identical as in claim 2.
8. according to claim 2, the preparation method described in 4,6 or 7, which is characterized in that the reaction temperature is 0 DEG C~80 DEG C.
9. according to claim 2, the preparation method described in 4,5,6 or 7, which is characterized in that the alkali is organic base or inorganic base,
The organic base is sodium alkoxide, and the inorganic base is sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, hydroxide
Potassium, hydrofining or sodium hydride.
10. the preparation method described according to claim 6 or 7, which is characterized in that the acid for adjusting acid to use in the process is inorganic
Acid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2719079A1 (en) * | 1977-04-29 | 1978-11-09 | Basf Ag | 3-Substd.-2-hydroxy-6-pyridone prodn. - from e.g. propiolic acid amide and substd. acetate ester, useful in dye mfr. |
| CN1753873A (en) * | 2003-02-22 | 2006-03-29 | 默克专利股份有限公司 | Cyanopyridone derivatives as liquid crystals |
| WO2007109459A2 (en) * | 2006-03-21 | 2007-09-27 | Janssen Pharmaceutica, Nv | Pyridines and pyridine n-oxides as modulators of thrombin |
-
2017
- 2017-01-21 CN CN201710044886.3A patent/CN108341771B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2719079A1 (en) * | 1977-04-29 | 1978-11-09 | Basf Ag | 3-Substd.-2-hydroxy-6-pyridone prodn. - from e.g. propiolic acid amide and substd. acetate ester, useful in dye mfr. |
| CN1753873A (en) * | 2003-02-22 | 2006-03-29 | 默克专利股份有限公司 | Cyanopyridone derivatives as liquid crystals |
| WO2007109459A2 (en) * | 2006-03-21 | 2007-09-27 | Janssen Pharmaceutica, Nv | Pyridines and pyridine n-oxides as modulators of thrombin |
Non-Patent Citations (4)
| Title |
|---|
| GEORGES BRAM,等: "N-Alkylation of pyrimidine and purine derivatives (uracils, xanthines, adenine) using solid/liquid phase-transfer catalysis without solvent", 《SYNTHESIS》 * |
| KOSAKU HIROTA,等: "A novel pyrimidine to pyridine ring transformation reaction. A facile synthesis of 2,6-dihydroxypyridines", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| KOSAKU HIROTA,等: "Pyrimidines. 17. Novel Pyrimidine to Pyridine Transformation Reaction. One-Step Synthesis of Pyrido[2,3-d]pyrimidines", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| YING HUANG,等: "Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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